Huntington's disease (HD) is a devastating autosomal dominant progressive neurodegenerative disorder. New therapies are being developed to slow disease progression or to delay its onset. Testing these compounds clinically is a major challenge because there are limited numbers of potential subjects either genetically at-risk for HD or already symptomatic. Currently, therapeutic trials in HD rely on clinical measures of diagnosis and progression, which are quite variable and also change relatively slowly and thus require large numbers of subjects and long periods of follow-up. There is a critical need to develop surrogate markers, such as neuroanatomic measures, which more precisely correlate with progression than variable clinical measures or which may be predictive of onset. Neuroimaging technology provides a way to prospectively examine the HD brain in vivo. We have developed novel neuro-imaging technologies that enable us to obtain highly accurate, reliable, and rapid morphometric measurements of progressive regional atrophy occurring in the entire brain. We have preliminary evidence that regional brain atrophy occurs in gene-positive presymptomatic individuals, permitting its detection and longitudinal assessment even before HD can be diagnosed clinically. By the time of diagnosis, atrophy is apparent in many cortical and subcortical regions and appears to occur in particular patterns, which likely correspond to the appearance of specific clinical features of the disease. Our data challenges the traditional focus on basal ganglia degeneration in HD, provides evidence for earlier and more extensive involvement of many additional brain regions, and greatly enriches the potential for brain imaging to help elucidate the structural basis of symptoms while providing relevant biological markers for response to neuroprotective therapies that can be tested in both symptomatic and presymptomatic patients. We propose to perform a prospective, longitudinal neuro-imaging study of presymptomatic and symptomatic individuals with HD to fully characterize the regional and progressive changes that occur throughout the disease. We will determine the sensitivity and reliability of our morphometric measures as surrogate markers of disease onset and disease progression in comparison to standard clinical measures to determine their potential as surrogate markers.